Flashcards in Pharmacokinetics Deck (39):
What is more important to biological action? Free drug or protein bound drug?
Movement from a site of administration to the systemic circulation
Movement of drug from the systemic circulation to perfused tissue and between tissue compartments
Biotransformation of the administered drug. Mainly hepatic, but other tissues metabolize also.
Removal of drugs and their metabolites from the body, mainly in bile or urine.
Only route of administration that bypasses the absorption process?
How does absorption occur?
Diffusion through membranes by small, nonpolar, uncharged molecules. Diffusion through aqueous intracellular spaces (capillary fenestrations). Less importantly: permeation through membrane channels and active transport using pumps.
C of a drug
Graphical difference between C in intravenous and extravascular administration
Intravenous = C is max at time of injection, decays afterwards.
Extravascular = Absorption time, C increases to a peak, then decays.
The fraction of an oral dose that reaches the systemic circulation. Can range from 0-1.
Factors that limit bioavailability
Incomplete absorption in the GI tract.
First pass metabolism by the liver (which can largely be evaded by routes of administration that aren't oral).
How to determine bioavailability from a graph?
Bioavailability can be determined by measuring the area under the curve(AUC) following a single dose, then comparing it to the AUC following the same dose administered IV.
Where in the GI tract are drugs absorbed?
Can happen anywhere, but the duodenum and the small intestine are the major site for absorption. Large surface area, longer transit time, pH in a range that leaves weak acids and bases largely non-polarized so it can pass through membranes.
Factors that influence drug distribution
Binding to plasma proteins (generally 95-99%). Vascularity of the tissue (drugs distribute most rapidly to highly perfused tissues.
Most important proteins for drug binding?
Albumin and alpha1-acid glycoprotein.
Distribution and redistribution
Drug leaves blood enters vessel rich group. Then will exit, enter blood, and enter other groups (muscle, adipose tissue).
Vd, why it's important
Volume of distribution. Important because a measurement of plasma concentration in the body underestimates the total amount that actually exists in the body. Drug has already migrated into tissues. Its a measure of the plasma volume that would need to exist if all of the drug was in the plasma.
Significance of Vd
High Vd means drug has accumulated in tissues. Low Vd means most of drug is in plasma.
Equation for Vd
Vd = A/C
A=total amount in body.
Does excretion of drug metabolites count as elimination?
NO! Elimination through excretion must occur to actual drug.
Rate of elimination
Mostly a first order process, that is related directly to plasma drug concentration. The higher the concentration, the higher the rate of elimination.
A constant that relates rate of elimination to plasma concentration.
Cl= rate of elimination/C in plasma.
What is maximum clearance for any organ?
Related to maximum perfusion. 1600 ml/min
900 hepatic, 720 renal.
Index of an organ's efficiency in eliminating a given drug. The fraction of the plasma that is cleared of the drug during each pass through the organ
Extraction Ratio Equation
E= (Cin-Cout)/Cin. Can range from 0-1
Clearance of a drug by an organ is based on...
Plasma flow to the organ and its extraction ratio.
Clearance of a drug by an organ equation.
High extraction drug?
E>=0.7 Clearance is limited by perfusion, so "Flow limited."
Low extraction drug?
E =<0.3 These are capacity limited. Reduced perfusion rate actually helps the extraction ratio.
Cl total = Cl hepatic + Cl renal + Cl other
Phase I reactions
Oxidation and reduction reactions that create a polar molecule. These reactions reduce activity of the parent drug, and increase likelihood of renal excretion.
Phase II reactions
Occur after phase I reactions, not catalyzed by CYP450s. Mostly take place in the cytoplasm and ER of hepatocytes. Add acetylene or glucuronate, acetate. Mostly all inactive, except with notable exceptions (morphine glucuronate).
What enzymes catalyze phase I reactions?
CYP450's located on hepatocytes, very important in the liver. Gi tract CYPs prevent absorption. A few are responsible for metabolizing most drugs.
Mainly high MW drugs and metabolites. Can be recycled to the liver through enterohepatic circulation.
Via glomerular filtration. Only unbound drug gets excreted and clearance is limited to GFR. Via secretion, which occurs in the proximal tubule.
Fraction excreted Unchanged
Renal Clearance of a drug excluding renal metabolism
Cl Renal = FEU * Clearance total